Vesicular Zn2+ is known to be toxic to neurons following its translocation from presynaptic release sites into the cytoplasm of postsynaptic cells that are destined to die. In addition to this extracellular source of Zn2+, we have observed that this metal can be released from intracellular metal binding proteins by thiol axidants. We have shown further that intracellularly liberated Zn2+ is a powerful apoptotic stimulus in neurons. Here, using molecular, cellular, and whole animal approaches, we propose to evaluate whether the release of intracellular Zn2+ represents a common feature in neuronal cell death following oxidative stress. The Specific Aims of this proposal are: 1. To determine whether peroxynitrite and nitric oxide trigger a neurotoxic cascade that results from the intracellular release of zinc in vitro. 2. To identify molecular components of the cell death pathway that are associated with the intracellular release of zinc in vitro. 3 To evaluate whether the intracellular release of zinc triggers apoptosis in an axotomy-induced in vivo model of neuronal cell death. Experiments described within these aims will test the hypothesis that the liberation of intracellular Zn2+ represents an important and ubiquitous trigger for cell death in neuronal injury. The long-term goal of this research program is to provide additional therapeutic targets to prevent or minimize neuronal cell death in the large number of neurological disorders associated with oxidative injury.